Involvement of Different Calcium Channels in the Depolarization‐Evoked Release of Noradrenaline from Sympathetic Neurones in Rabbit Carotid Artery*

Uhrenholt, Torben Rene; Nedergaard, Ove A.

doi:10.1111/j.1742-7843.2005.pto_90.x

Cited by 7 publications

(6 citation statements)

References 33 publications

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“…In neurons, the Ca V ␤ 3 is primarily associated with the ␣ 1B subunit to form N-type Ca 2+ channels [14] . Specifi cally, blockade of N-type Ca 2+ channels inhibits norepinephrine release from sympathetic nerves [24, 25,30] . Targeted deletion of the ␣ 1B subunit exhibited a marked reduction in barorefl ex response to carotid occlusion [23] .…”

Section: Discussionmentioning

confidence: 99%

Involvement of Voltage-Dependent Ca2+ Channel β3 Subunit in the Autonomic Control of Heart Rate Variability

Wu¹,

Ono²,

Murakami³

et al. 2006

Pharmacology

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Noradrenaline release from sympathetic nerve terminals is dependent on Ca²⁺ entry through neuronal voltage-gated N-type Ca²⁺ channels. The accessory β₃ subunits of Ca²⁺ channels (Ca_Vβ₃) are preferentially associated with the α_1B subunit to form N-type Ca²⁺ channels, and are therefore expected to play a functional role in the stimulation-evoked release of noradrenaline. In this study, we employed Ca_Vβ₃-null, Ca_Vβ₃-overexpressing (Ca_Vβ₃-Tg), and wild-type (WT) mice to investigate the possible roles of Ca_Vβ₃ in the sympathetic regulation of heart rate in vivo. Telemetry was used to monitor the ECG and both time and frequency domain analyses were carried out to evaluate heart rate variability. In the frequency domain analysis, power spectral density of the RR interval series was computed using the fast Fourier transform algorithm. The resting heart rate was increased in Ca_Vβ₃-Tg mice compared with both Ca_Vβ₃-null and WT mice. Mice overexpressing Ca_Vβ₃ displayed decreased heart rate variability, which was measured by the time domain analysis of the standard deviation of RR intervals. In the frequency domain analysis, Ca_Vβ₃-Tg mice showed decreased spectral powers compared with WT and Ca_Vβ₃-null mice. Pharmacological blockade of β-adrenergic receptors with metoprolol decreased the heart rate in all genotypes, but the extent of the decrease was most obvious in Ca_Vβ₃-Tg mice. On the other hand, the spectral powers were decreased in response to parasympathetic blockade (atropine) in WT and Ca_Vβ₃-Tg mice. These results indicate the functional roles of Ca_Vβ₃ in regulating sympathetic nerve signaling.

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Section: Discussionmentioning

confidence: 99%

Involvement of Voltage-Dependent Ca2+ Channel β3 Subunit in the Autonomic Control of Heart Rate Variability

Wu¹,

Ono²,

Murakami³

et al. 2006

Pharmacology

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“…In both carotid body and postganglionic sympathetic nerve terminals, for example, release triggered through N-type channel activation is actually higher at lower stimulation frequencies (0.4 -2 Hz) than at higher frequencies (30 Hz). 58 In other sympathetic neurons (e.g., noradrenergic constrictions of the inferior vena cava and uterine artery), there is no affect of stimulation frequency on N-type channel-dependent release, whereas in still other cells sympathetic-mediated vasoconstriction does not appear to involve N-type channelmediated release. 59 In one homozygous N-type channel gene knockout strain, it was found that heart rate and blood pressure were unaffected by the complete lack of N-type channels, whereas in another independent strain both heart rate and blood pressure were elevated.…”

Section: Can Prialt Be Improved Upon? the Case For Identifying Orallymentioning

confidence: 99%

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

2005

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Summary:The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The Ntype calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Prialt for the treatment of intractable pain. Prialt is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Prialt, and outlines possible strategies to improve upon Prialt's relatively narrow therapeutic window.

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“…Spatial and intensity correlation of neuronal Cav2 with VNUT and VMAT2. Specific Cav2 isoforms mediate the preferential release of NE or ATP from perivascular nerves, suggesting a preferential spatial association between specific Cav2 isoforms and segregated pools of transmitter-specific vesicles (14,43,54). We tested whether such a relationship could be observed by optical microscopy.…”

Section: Resultsmentioning

confidence: 99%

VNUT and VMAT2 segregate within sympathetic varicosities and localize near preferred Cav2 isoforms in the rat tail artery

Kalkhoran

Chow

Walia

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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ATP and norepinephrine (NE) are coreleased from peripheral sympathetic nerve terminals. Whether they are stored in the same vesicles has been debated for decades. Preferential dependence of NE or ATP release on Ca2+ influx through specific voltage-gated Ca2+ channel (Cav2) isoforms suggests that NE and ATP are stored in separate vesicle pools, but simultaneous imaging of NE and ATP containing vesicles within single varicosities has not been reported. We conducted an immunohistochemical study of vesicular monoamine transporter 2 (VMAT2/SLC18A2) and vesicular nucleotide translocase (VNUT/SLC17A9) as markers of vesicles containing NE and ATP in sympathetic nerves of the rat tail artery. A large fraction of varicosities exhibited neighboring, rather than overlapping, VNUT and VMAT2 fluorescent puncta. VMAT2, but not VNUT, colocalized with synaptotagmin 1. Cav2.1, Cav2.2, and Cav2.3 are expressed in nerves in the tunica adventitia. VMAT2 preferentially localized adjacent to Cav2.2 and Cav2.3 rather than Cav2.1. VNUT preferentially localized adjacent to Cav2.3 > Cav2.2 >> Cav2.1. With the use of wire myography, inhibition of field-stimulated vasoconstriction with the Cav2.3 blocker SNX-482 (0.25 µM) mimicked the effects of the P2X inhibitor suramin (100 µM) rather than the α-adrenergic inhibitor phentolamine (10 µM). Variable sensitivity to SNX-482 and suramin between animals closely correlated with Cav2.3 staining. We concluded that a majority of ATP and NE stores localize to separate vesicle pools that use different synaptotagmin isoforms and that localize near different Cav2 isoforms to mediate vesicle release. Cav2.3 appears to play a previously unrecognized role in mediating ATP release in the rat tail artery. NEW & NOTEWORTHY Immunofluorescence imaging of vesicular nucleotide translocase and vesicular monoamine transporter 2 in rat tail arteries revealed that ATP and norepinephrine, classical cotransmitters, localize to well-segregated vesicle pools. Furthermore, vesicular nucleotide translocase and vesicular monoamine transporter 2 exhibit preferential localization with specific Cav2 isoforms. These novel observations address long-standing debates regarding the mechanism(s) of sympathetic neurotransmitter corelease.

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Involvement of Different Calcium Channels in the Depolarization‐Evoked Release of Noradrenaline from Sympathetic Neurones in Rabbit Carotid Artery*

Abstract: Abstract:The calcium channels coupled to noradrenaline release from sympathetic neurones in the rabbit isolated carotid artery were examined. Rings of carotid artery were preloaded with (-)-[

Cited by 7 publications

References 33 publications

Involvement of Voltage-Dependent Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit in the Autonomic Control of Heart Rate Variability

Involvement of Voltage-Dependent Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit in the Autonomic Control of Heart Rate Variability

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

VNUT and VMAT2 segregate within sympathetic varicosities and localize near preferred Cav2 isoforms in the rat tail artery

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